Alpha-substituted-(2,5-diacyloxyphenyl) acetaldehyde



U.S. Cl. 260-476 United States Patent 3,501,519a-SUBSTITUTED-(2,5-DIACYLOXYPHENYL) ACETALDEHYDE Louis L. Skaletzky,Kalamazoo, Mich., asslgnor to The Upjohn Company, Kalamazoo, Mich., acorporation of Delaware No Drawing. Original application Sept. 25, 1964,Ser. No. 399,368, now Patent No. 3,412,109, dated Nov. 19, 1968. Dividedand this application June 19, 1968, Ser. No. 738,095

Int. Cl. C07c 69/78, 69/24 4 Claims ABSTRACT OF THE DISCLOSURE Summaryof the invention This application is a division of application Ser. No.399,368 filed Sept. 25, 1964 and now US. Patent No. 3,412,109, datedJan. 19, 1968.

This invention pertains to novel organic chemical compounds, and to aprocess for preparing the same. The invention is more particularlydirected to novel 2-loweralkoxy 2,3-dihydro-3-substituted-S-benzofuranols, novel a substituted-(2,5-dihydroxyphenyl)acetaldehyde diacylate intermediates, and a process for preparing thesame.

Detailed description of the invention The novel 2lower-alkoxy-Z,3-dihydro-3-substituted-5- benzofuranols of thisinvention have the structural formula:

wherein R is selected from the group consisting of hydrogen,loWer-alkyl, and phenyl; and R is selected from the group consisting oflower-alkyl and phenyl.

The novel a substituted (2,S-dihydroxyphenyDacetaldehyde diacylateintermediates of this invention have the structural formula:

Acyl

wherein R and R are as defined above, and Acyl is anyhydrocarboncarboxylic acyl radical, conveniently one of from 1 to 8carbon atoms, inclusive.

In accordance with the process of the invention, the

3,501,519 Patented Mar. 17, 1970 novel 2-1oWer-alkoxy-2,3-dihydro-3-substituted-5-benzofuranols of Formula I and the novela-substituted-(2,5 dihydroxyphenyl)-acetaldehyde diacylate intermediatesof Formula II are prepared from 2-amino-2,3-dihydro-3-substituted-S-benzofuranols of the formula:

(III) wherein R and R are as previously defined; R and R takenseparately are selected from the group consisting of lower-alkyl,phenyl, and substituted phenyl selected from the group consisting ofloweralkylphenyl, lower-alkoxyphenyl, and halophenyl, provided that Rand R are not simultaneously selected from phenyl and substitutedphenyl; and R and R taken together with constitute a saturatedheterocyclic amino radical of from 5 to 7 nuclear atoms, inclusive,wherein Z is a saturated bivalent radical selected from the groupconsisting of alkylene, oxadialkylene, thiadialkylene, and N-lower-alkylazadialkylene.

As employed herein, the term lower-alkyl includes methyl, ethyl, propyl,butyl, pentyl, hexyl, and isomeric forms thereof. The term lower-alkoxyincludes methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, andisomeric forms thereof. The term halophenyl includes, for example,o-fiuorophenyl, p-bromophenyl, 3,5-dichlorophenyl, 3, 4,S-tribromophenyl, m-iodophenyl, o-chlorophenyl, and the like. Andfinally, the term saturated heterocyclic amino radical m -N Z of from 5to 7 nuclear atoms, inclusive, includes, for example, pyrrolidinyl,2-methylpyrrolidinyl, Z-ethylpyrrolidinyl, 2, Z-dimethyl-pyrrolidinyl,3, 4-dimethylpyrrolidinyl, 2-isopropylpyrrolidinyl, 2-sec.butylpyrrolidinyl, and like alkylpyrrolidinyl groups, morpholino,2-ethy1- morpholino, 2-ethyl-S-methylmorpholino,3,3,-dimethylmorpholino, thiamorpholino, 3-methylmorpholino, 2, 3,6-trimethylmorpholino, 4-methylpiperazinyl, 4-butylpiperazinyl,piperidino, 2-methylpiperidino, B-methylpiperidino, 4-methylpiperidino,4-propylpiperidino, 2-propylpiperidino, 4-isopropylpiperidino, and likealkylpiperidino groups, hexamethylenimino, Z-methylhexamethylenimino, 3,6-dimethylhexamethylenimino, homomorpholino, and the like.

The novel compounds of Formula I are useful for a variety of purposes.For example, the compounds are useful as intermediates for reaction withphosgene to produce the corresponding chloroformates Which in turn arereacted with ammonia, monomethylamine, dimethylamine, or any otherprimary or secondary amines to produce corresponding carbamates usefulas insecticides. Insecticidal carbamates can also be prepared byreacting the compounds of Formula I with isocyanates such as methylisocyanate, ethyl isocyanate, and the like.

The 2 1oWer-alkoxy-2,3-dihydro-3,3-di-lower-alkyl-5- benzofuranols ofFormula I have been found to be pharmacologically active as sedatives.They can 'be used as central nervous depressants in mammals, birds andother animals, e.g., mice, rats, and dogs. The compounds of Formula Iare also useful as antioxidants.

The novel tit-substituted-(2,5-dihydroxyphenyl)acetaldehyde diacylateintermediates (compounds of Formula II) are prepared from the2-amino-2,3-dihydro-3-substituted- S-benzofuranols of Formula III byreaction with a hydrocarboncarboxylic acid halide. It has been found, inaccordance with the novel process of the invention, that not onlyesterification occurs, but also removal of the 2-amino group, cleavageof the dihydrofuran ring, and resultant formation of antit-substituted-(2,5-dihydroxyphenyl)-acetaldehyde diacylate. Thetransformation of a 2-amino-2,3- dihydro-3-substituted-S-benzofuranolinto an Ot-SubStitHted-(2,5-dihydroxyphenyl)acetaldehyde diacylate iseffected with an excess of hydrocarboncarboxylic acid halide in thepresence of an organic solvent medium and an acid acceptor (water mustbe excluded). A reaction temperature in the range of about C. to about30 C. is convenient although lower and slightly higher temperatures canbe used if desired. Suitable organic solvents include, for example,pyridine, ethylene dichloride, ether, benzene, toluene, and the like.Suitable acid acceptors include, for example, pyridine, triethylamine,N,N-dimethylaniline, picoline, lutedine, and the like. Thea-substituted(2,5-dihydroxyphenyl)acetaldehyde diacylate is recovered byconventional procedures. Illustratively, excess hydrocarbon carboxylicacid halide is decomposed by pouring the reaction mixture into water(preferably ice-water), and the water insoluble diester is recovered byany of several conventional methods.

For example, when a water-miscible organic solvent (e.g., pyridine) isused as a reaction medium, the product separates directly from the watermixture and can be recovered as a solid or oil. On the other hand, whena water-immiscible organic solvent (e.g., benzene) is used, the productis in solution in the organic layer and can thus be separated forfurther purification. Illustratively, the organic solvent is removed byevaporation or distillation and the residue is purified. Anu-substituted-(2,5- dihydroxyphenyl)acetaldehyde diacylate can also berecovered from an organic solvent by chromatographic procedures. It isfurther purified by conventional procedures, for example, distillationand crystallization.

Although any hydrocarboncarboxylic acid halide can be used in theforegoing reaction, convenient suitable ones include acetyl chloride,propionyl chloride, butyryl bromide, caproyl chloride, capryloylchloride, benzoyl chloride (preferred), phenyacetyl chloride, and thelike.

The novel 2-lower-alkoxy-2,3-dil1ydro-3-substituted-5- benzofuranols(compounds of Formula I) are prepared from the onsubstituted-(2,5-dihydroxyphenyl)acetaldehydediacylate intermediates ofFormula II by reaction of the diester-aldehyde with an alkanol and analkali metal alkoxide or hydroxide. This reaction effects an unexpectedresult in the reformation of the 2,3-dihydrobenzofurano1 structure andsubstitution of an alkoxy group in the 2- position of the2,3-dihydrobenzofuranol. The reaction proceeds at a temperature in therange of about to about 100 C., conveniently at a temperature of about50 to about 80 C. Suitable alkali metal alkoxides and hydroxidesinclude, for example, sodium methoxide, sodium ethoxide, potassiumethoxide, sodium butoxide, sodium hexoxide, sodium hydroxide, potassiumhydroxide, and the like. When an alkali metal alkoxide is used, thereaction mixture should be anhydrous, but when an alkali metal hydroxideis used, the reaction mixture can be aqueous. In general, it ispreferred to use at least 3 molar amounts of the alkali metal alkoxideor hydroxide per molar amount of the diester-aldehyde. A preferredreaction mixture consists of the diester-aldehyde, an alkali metalhydroxide, an alkanol, and a small amount of water.

The 2 lower-alkoxy-2,3-dihydro-3-substituted-5-benzofuranol is recoveredby conventional procedures such as neutralizing the reaction mixture,evaporating the reac- 4 tion medium, dilution with Water, solventextraction, drying, evaporation, chromatographic purification andcrystallization.

The novel 2-lower-alkoxy-2,3-dihydro-3-substituted-5- benzofuranols ofFormula I are also prepared from the2-amino-2,3-dihydro-3-substituted-5-benzofuranols of Formula III byeither of: (1) reaction with a quaternizing reagent, for example, analkyl halide .or a dialkyl sulfate in the presence of an alkanol, or (2)by heating with strong mineral acid in the presence of an alkanol.

When an alkyl halide or a dialkyl surfate is used, the reaction mixturecontaining a 2-amino-2,3-dihydro-3- substituted-S-benzofuranol is heatedat a temperature in the range of about 50 to about 125 C., care beingtaken to prevent loss of volatile components of the reaction mixture. Areaction temperature in the range of about 70 to about C. is preferred.The reaction proceeds relatively slowly and requires about 24 to about72 hrs. for substantial completion. The lower reaction temperaturesrequire more time than the higher reaction temperatures in accordancewith well-known timeztemperature relationships. In general, an excess ofalkyl halide or dialkyl sulfate is used; conveniently, from about 1.5 toabout 5 molar equivalents for each mole of the Z-amino-2,3-dihydro-3substituted-S-benzofuranol. Suitable alkyl halides include,for example, methyl iodide (preferred), ethyl iodide, propyl iodide,butyl iodide, methyl bromide, and the like. The alkyl iodides are morereactive than alkyl bromides, which, in turn, are more reactive thanalkyl chlorides. Suitable dialkyl sulfates include, for example,dimethyl sulfate (preferred), diethyl sulfate, diisopropyl sulfate,dibutyl sulfate, and the like. Suitable alkanols for the reaction andfor the 2-lower-alkoxy substituent of Formula I include, for example,methanol, ethanol, propyl alcohol, isopropyl alcohol, butyl alcohol,pentyl alcohol, hexyl alcohol, and the like. The 2-loWeralkoxy2,3-dihydro-3-substituted-S-benzofuranol product is recovered byremoving teh excess alkanol and purifying the product by conventionalprocedures such as chromatography. and crystallization.

When a strong mineral acid and an alkanol are used, the reaction mixtureis heated, for example, at the reflux temperature of the alkanol, untilthe reaction is completed. Any strong mineral acid can be used, forexample, concentrated hydrochloric acid, concentrated sulfuric acid, andconcentrated phosphoric acid. In general, the product is recovered byconventional methods, for example, removing the alkanol by evaporation,extracting the 2-loWer-alkoxy-2,3-dihydro-3-substituted-5-benzofuranolwith an organic solvent, washing with water to remove the amine saltformed in the reaction, neutralizing any strong acid present in theextract, drying, distillation, and crystallization.

The 2 amino-2,3-dihydro-3-substituted=5-benzofuranol starting compoundsaccording to Formula III are prepared by condensing a (l-alkenyl) amineof the formula:

R1 R3 RP=CHN wherein R R R and R are as previously defined andp-benzoquinone, advantageously in the presence of an inert solvent andunder substantially anhydrous conditions. Reaction of about equimolaramounts of the reactants is preferred, although an excess of the(l-alkenyl) amine can be employed if desired. The condensation reactionis exothermic, and the reaction mixture undergoes an initial evolutionof heat. In some circumstances, depending somewhat on quantities andconcentration of reactants and rate of mixing, the temperature of thereaction mixture will reach the boiling temperature. After the initialreaction subsides, the reaction is completed at about 25 C.; although itcan also be completed at temperatures higher than 25 C. if desired, suchas up to about 80 C. or even higher. Ordinarily, satisfactory yields areobtained after about hrs. to about 48 hrs. at about C.; but if desired,longer reaction times can be employed. Since the reaction is sometimesvigorously exothermic, it is often preferred to mix the reactants at atemperature in the range about 4 to about 10 C. and then permit thereaction mixture to warm to about 25 C. for completion of the reaction.Suitable inert solvents for the reaction include benzene, ethyl acetate,toluene, hexane, ether, tetrahyrdofuran, dioxane, chloroform, carbontetrachloride, acetonitrile, and the like.

, The 2-amino-2,3-dihydro-3-substituted-S-benzofuranols usually separatefrom the reaction mixture as solids and Example l.-Preparation of2,3-dihydro-3,3-dimethyl-2- ethoxy-S-benzofuranol (Part A)2,3-dihydro-3,3-dimethyl-2-piperidino-S-benzofuranol.A solution of 43 g.(0.31 mole) of 1-(2- methylpropenyl)-piperidine in 100 ml. of benzenewas added to a solution of 32.5 g. (0.30 mole) of p-benzoquinone in 300ml. of benzene. The spontaneous exothermic reaction which accompaniedthe mixing increased the temperature and the mixture darkened. As thereaction mixture cooled, brown crystals began to appear as thetemperature approached 25 C. After setting the mixture aside atabout 25C. for 2 days, the brown crystals were collected on a filter, andrecrystallized from benzene. There was thus obtained 51 g. (69% yield)of 2,3-dihydro-' 3,3-dimethyl-2-piperidino-S-benzofuranol having amelting point of 157 to 158 C. A cream=colored analytical sample wasobtained by recrystallization from a mixture of benzene and technicalhexane (Skellysolve B, a mixture of isomeric hexanes having a boilingrange of 140 to 160 F.). The melting point was 159 to 160 C.

Analysis.Calcd. for C H iNO (percent): C, 72.84; H, 8.56; N, 5.66. Found(percent): C, 72.83; H, 8.29; N, 5.37.

(Part B) u,u-dirnethyl-(2,5-dihydroxyphenyl)acetaldehyde dibenzoate. Asolution of 50 g. (0.2 mole) 2,3-dihydro-3,3-dimethyl-2-piperidino-S-benzofuranol (Part A above) and 100ml. benzoyl chloride in 500 ml. pyridine was kept at about 25 C. for 5hrs. The reaction mixture was poured into ice-water and the mixture wasset aside until an oil that had separated solidified. The solid wasrecovered on a filter, washed with water, and dissolved in chloroform.The chloroform solution was washed successively with dilute hydrochloricacid and aqueous sodium bicarbonate, and dried over anhydrous magnesiumsulfate. After removing the chloroform by evaporation under reducedpressure, the residue was recrystallized two times from a mixture ofbenzene and technical hexane to give 65.2 g. (83% yield) ofa,ot-dimethyl-(2,5-dihydroxyphenol)acetaldehyde dibenzoate having amelting point of 141 to 142 C. An analytical sample recrystallized froma mixture of benzene and technical hexane had a melting point of 143 to144 c.

Analysis.Calcd. for C H O (percent): C, 74.21; H, 5.19. Found (percent):C, 74.43; H, 5.51.

(Part C) 2,3-dihydro-3,3-dimethyl-2-ethoxy-S-benzofuranol.-A reactionmixture consisting of 11.0 g. m x-dimethyl (2,5dihydroxyphenyl)acetaldehyde dibenzoate (Part B above), 200 ml. ethanol(95%), 15 ml. water, and 20.0 g. aqueous sodium hydroxide by weight) washeated at the reflux temperature for /2 hr. The reaction mixture wascooled, 15 ml. of glacial acetic acid was added, and the solvent wasremoved by evaporation under reduced pressure. The residue thus obtainedwas dispersed in a mixture of ether and water and the ether layer wasseparated. The ether solution was washed with water, sodium bicarbonatesolution, dried over anhydrous magnesium sulfate, and the ether removedby-evaporation. There was thus obtained 6.6 g. of an oil. It wasdissolved in methylene chloride and the solution was poured into acolumn of magnesia silica gel adsorbent (Florisil). After eluting thecolumn with a mixture of acetone and technical hexane (1:19 by volume)and evaporating the solvents from the eluate, there was obtained 4.5 g.(76% yield) of 2,3-dihydro-3,3-dimethyl-2-ethoxy-5-benzofuranol having amelting point of 73 to 74 C. One recrystallization from a mixture ofether and pentane gave the compound as a white solid having a meltingpoint of 74 to 75 C.

Analysis.Calcd. for C H O (percent): C, 69.21; H, 7.74. Found (percent):C, 69.15; H, 7.74.

Example 2.Preparation of 2,3-dihydro-2-ethoxy-3-isopropyl-S-benzofuranol(Part A) 2,3-dihydro-3-isopropyl-2-piperidino-5-benzofuranol.A solutionof 21.5 g. (0.2 mole) of p-benzoquinone and 30.5 g. (0.2 mole) of1-(3-methyl-1-butenyl)- piperidine in 400 ml. of benzene was set asideat about 25 C. for 3 days. A brown solid that separated was collected ina filter and recrystallized from a mixture of benzene and technicalhexane to give 28 g. (54% yield) of2,3-dihydro-3-isopropyl-Z-piperidino-S-benzofuranol having a meltingpoint of 152 to 158 C. Two recrystallizations from benezene gave ananalytical sample melting at 156 to 158 C.

Analysis.Calcd. for C H NO (percent): C, 73.53; H, 8.87; N, 5.36. Found(percent): C, 73.43; H, 8.90; N, 5.28.

(Part B)a-isopropyl-(2,5-dihydroxyphenyl)acetaldehydedibenzoate.-Following theprocedure of Example 1, Part B, but substituting2,3-dihydro-3-isopropyl-2-piperidino-5-benzofuranol for2,3-dihydro-3,3-dimethyl-2-piperidino-S-benzofuranol, there was prepareda-isopropyl- (2,5-dihydroxyphenyl)acetaldehyde dibenzoate.

(Part C) 2,3 -dihydro-2-ethoxy-3-isopropyl-5-benzofuranch-Following theprocedure of Example 1, Part C, but substituting a. isoropyl(2,5-dihydroxyphenyl)acetaldehyde dibenzoate fora,a-dimethyl-(2,5-dihydroxyphenyl)-acetaldehyde dibenzoate, there wasprepared 2,3- dihydro-2-ethoxy-3-isopropyl-S-benzofuranol.

Example (Part A) 2,3-dihydro-3-phenyl-2-piperidino-5-benzofuranolhydrochloride.A reaction mixture consisting of 5.4 g. (0.05 mole) ofp-benzoquinone and 9.5 g. (0.05 mole) of l-styrylpiperidine in ml. ofethyl acetate was set aside at about 25 C. for 24 hrs. The mixture wasthen concentrated by evaporating the solvent under reduced pressure. Theresidue thus obtained was dissolved in ether and the ether solution wastreated with ethereal hydrogen chloride. A precipitate that formed wascollected on a filter and recrystallized from absolute ethanol to give3.9 g. of 2,3-dihydro-3-phenyl-2-piperidino-S-benzofuranol hydrochloridehaving a melting point of 222 to 225 C. [with decomposition (yellowing)at 215 C.]. The compound was recrystallized three times from a mixtureof methanol and ether, and it had a melting point of 222 to 224 C. (withdecomposition).

Analysis.Calcd. for C H NO .HCl (percent): C,

2-piperidino-5-benzofuranol, there was prepared a-phenyl(2,5-dihydroxyphenyl)-acetaldehyde dibenzoate.

(Part C) 2,3 dihydroXy-2-ethoxy-3-pheny1-5-benz0furanol.Following theprocedure of Example 1, Part C, but substitutinga-phenyl-(2,5-dihydroxypenyl)acetaldehyde dibenzoate fora,a-dimethyl-(2,5-dihydroxyphenyl)- acetaldehyde dibenzoate, there wasobtained 2,3-dihydro- 2-ethoxy-3-phenyl-5-benzofuranol.

Example 4.-Preparation of 2,3-dihydro-2-ethoxy-3-ethyl- S-benzofuranol(Part A) 2,3 -dihydro-3-ethyl-2-piperidino-5-benzofu ranol.A solution of10.8 g. (0.1 mole) of p-benzoquinone and 14.0 g. (0.1 mole) of1-(1butenyl)piperidine in 250 ml. of benzene was set aside at about 25C. for about 20 hrs. The solid that had separated was collected on afilter and recrystallized from ethyl acetate using an activated carbonfor decolorization. There was thus obtained 8.9 g. of2.3-dihvdro-3-ethyl-2-piperidino-5-benzofuranol having a melting pointof 175 to 184 C. After two more recrystallizations from ethyl acetatethe compound was obtained as a pinkish-white solid having a meltingpoint of 176 to 183 C.

Analysis.Calcd for C H NO (percent): C, 72.84; H, 8.56; N, 5.66. Found(percent): C, 72.69; H, 8.96; N, 5.50.

(Part B) a-ethyl-(2,5-dihydroxyphenyl)acetaldehyde dibenzoate.Fo1lowingthe procedure of Example 1, Part B, but substituting2,3-dihydro-3-ethyl-2-piperidino- 5-benzofuranol for2,3-dihydro-3,3-dimethyl-2-piperidino- S-benzofuranol, there wasprepared a-ethyI-(LS-dihydroxyphenyl) acetaldehyde dibenzoate.

(Part C) 2,3 dihydro 2-ethoxy-3-ethyl-5-'benzofuranol.Fol1owing theprocerdure of Example 1, Part C, but substitutingu-ethyl-(2,5-dihydroxyphenyl)acetaldehyde dibenzoate fora,u-dimethyl-(2,5-dihydroxphenyl) acetaldehyde dibenzoate, there wasprepared 2,3-dihydro- 2-ethoxy-3-ethyl-5-benzofuranol.

Example 5.Alternative preparation of 2,3dihydro-3,3dimethyl-Z-ethoxy-5-'benzofurano1 A solution consisting of g. of2,3-dihydro-3, 3-dimethyl-2-piperidino-S-benzofuranol (Example 1, PartA), 10 ml. concentrated sulfuric acid (18 M), and 200 ml. absoluteethanol was heated at the reflux temperature for 2 /2 days. Aftercooling, most of the ethanol was removed by evaporating under reducedpressure, and the residue was dissolved in a mixture of ether and water.The ether layer was separated from the aqueous layer, washed withaqueous sodium bicarbonate, and dried over anhydrous magnesium sulfate.After removing the ether by evaporation, an oil that remained wasdistilled at 131 to 132 C. and 1.0 to 1.1 mm. of mercury pressure. Therewas thus obtained. 6.02 g. (71% yield) of2,3-dihydro-3,3-dimehyl-2-ethoxy-5-dibenzofuranol as a viscous oil whichcrystallized when triturated in the presence of seed crystals, with amixture of ether and pentane. The product was thus obtained as a whitesolid having a melting point of 73 to 75 C.

Example 6 (Part A)2,3-dihydro-3,3dimethyl-2-(4-methyl-1-piperazinyl)-5-benzofuranol.-Asolution of 38 g. (0.35 mole) of p-benzoquinone and 55.5 g. (0.36 mole)of 1-(2- methylpropenyl)-4-methylpiperazine in 600 ml. of benzene wasset aside at about 25 C. for 24 hours. A brown solid that separated wascollected on a filter and the filter cake was washed with technicalhexane. There was thus obtained 63 g. (68.5% yield) of2,3-dihydro-3,3-di- 8 methyl 2 (4 methyl 1 piperazinyl) 5 benzofura-1101 having a melting point of 184 to 186 C. After tworecrystallizations from ethyl acetate the compound had a melting pointof 195 C.

Analysis.Calcd for C H N O (percent): C, 68.87; H, 8.45; N, 10.68. Found(percent): C, 68.42; H, 8.36; N, 10.72.

(Part B) 2,3 dihydro 3,3-dimethyl-2-ethoxy-5-benzofuran0l.Following theprocedure of Example 5, but substituting 2,3 dihydro 3,3dimethyl-2-(4-methyl-1 piperazinyl)-5-benzofuranol for2,3-dihydro-3,3-dimethyl- 2-piperidino-S-benzofuranol, there wasprepared 2,3-dihydro-3,3-dimethyl-2-ethoxy-S-benzofuranol.

Example 7 (Part A) 2,3 dihydro 3,3-dimethyl-2-morpholino-5-benzofuranol.A solution of 10.5 g. (0.098 mole) of pbenzoquinone and14.0 g. (0.1 mole) of 4-(2-methyl propenyl)morpholine in 250 ml. ofbenzene was set aside at about 25 C. for 3 days. A red solid thatseparated was collected on a filter, and the filter cake was trituratedwith hot methylene chloride. After again collecting the solid on afilter, it was recrystallized two times from ethyl acetate to give 4.8g. of 2,3-dihydro-3,3-dimethyl-2-morpholino-S-benzofuranol having amelting point of 187 to 189 C. An analytical sample obtained byrecrystalliza tion from ethyl acetate had a melting point of 187 toAnalysis.Calcd for C H NO (percent): C, 67.44; H, 7.68; N, 5.62. Found(percent): C, 67.74; H, 7.83; N, 5.58.

(Part B) 2,3 dihydro 3,3-dimethyl-Z-ethoxy-S-benzofuranoL-Following theprocedure of Example 5, but substituting 2,3 dihydro3,3-dimethyl-Z-morpholino-S- 'benzofuranol for2,3-dihydro-3,3-dimethyl-2 piperidino-5- benzofuranol, there wasprepared 2,3-dihydro-3,3-dimethyl-Z-ethoxy-S-benzofuranol.

Example 8.Alternative preparation of 2,3-dihydro-3,3-

dimethyl-Z-ethoxy-S-benzofuranol A mixture consisting of 10 g.2,3-dihydro-3,3-dimethyl- 2-piperidino-5-benzofuranol, 20 ml. methyliodide, and 50 ml. of absolute ethanol was heated on a steam bath in asealed tube for 16 hrs. The ethanol was removed from the reactionmixture by evaporation under reduced pressure. The residue was dissolvedin methylene chloride, and the solution was poured onto a column ofmagnesia silica gel adsorbent (Florisil) The column was eluted with amixture of acetone and technical hexane (1:9 by volume), and the eluatewas concentrated by evaporating the solvent under reduced pressure.There was thus obtained 3.2 g. of2,3-dihydro-3,3-dimethyl-2-ethoxy-5-benzofuranol having a melting pointof 74 to 75 C.

Example 9 (Part A) 2,3 dihydro-3,3-dimethyl-2-(l-pyrrolidinyl)-S-benzofuranoL-A solution of 10.5 g. (0.098 mole) of p-benzoquinone and12.5 g. (0.1 mole) of 1-(2-methylpropenyl)pyrrolidine in 250 ml. ofbenzene was set aside at about 25 C. for 24 hrs. A precipitate thatformed was collected on a filter, and recrystallized two times fromethyl acetate. There was thus obtained 8.6 g. of 2,3-dihydro 3,3dimethyl-2-(l-pyrrolidinyl)-5-benzofuranol having a melting point of 154to 155 C. After a third recrystallization from ethyl acetate ananalytical sampl melting at 154 C. was obtained.

Analysise-Calcd for C H NO '(percent): C, 72.07; H, 8.21; N, 6.00. Found(percent): C, 72.07; H, 8.21; N, 5.72.

(Part B) 2,3 dihydro 3,3-dimethyl-2-ethoxy-5-benzofuranol.Following theprocedure of Example 8, but substituting 2,3 dihydro3,3-dimethyl-2-(1-pyrrolidinyl)-5- benzofuranol for2,3-dihydro-3,3-dimethy1-2-piperidino-5- benzofuranol, there wasprepared 2,3-dihydro-3,3-dimethyl-Z-ethoxy-S-benzofuranol.

4. The process which comprises reacting a 2-amino-2,3-dihydro-3-substituted-S-benzofuranol of the formula:

HO- R2 of from 5 to 7 nuclear atoms, inclusive, wherein Z is a saturatedbivalent radical selected from the group consisting of alkylene,oxadialkyl ene, thiadialkylene, and N- lower-alkylazadialkylene with ahydrocarboncarboxylic acid halide of from 1 to 8 carbon atoms, in thepresence of an inert organic solvent and an acid acceptor, to pro- 14duce an a-substituted-(2,5-dihydroxyphenyl)acetaldehyd diacylate of theformula:

Acyl

1 +CHO R2 Acyl wherein R and R are as defined and Acyl is the acyradical of the hydrocarboncarboxylic acid.

References Cited UNITED STATES PATENTS 7/1968 Hosler 26045.85 5/1965Brannock 260247J LORRAINE A. WEINBERGER, Primary Examiner EDWARD JAYGLEIMAN, Assistant Examiner US. Cl. X.R.

